Field
The present disclosure relates generally to a protocol to treat or prevent diseases or conditions associated with pathological forms of amyloid beta (Aβ), including Alzheimer's disease. Enabled herein is a reagent for use in the treatment and prophylaxis and diagnosis of Aβ-associated pathological conditions.
Prior Art
Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.
Alzheimer's disease is a degenerative brain disorder characterized histologically by neuritic plaques found primarily in association with the cortex, limbic system and basal ganglia. These neuritic plaques comprise a cleavage product of amyloid precursor protein (APP), a type I transmembrane glycoprotein.
The cleavage product of APP is β-amyloid peptide or Aβ. Incorrect processing of APP can result in pathological forms of Aβ (Tanzi et al. (1996) Neurobiol Dis 3:159-168; Hardy (1996) Ann Med 28:255-258; Schenk et al. (1999) Nature 400:173-177). These pathological forms include Aβ1-42 and Aβ1-43 which have been detected as predominant species in the neurite plaques.
Bard et al. (2000) Nature Medicine 6:916-919 showed that peripheral administration of antibodies directed against Aβ can reduce plaque burden. Bard et al. (2003) Proc. Natl. Acad. Sci. USA 100:2023-2028 subsequently showed that Fc-mediated phagocytosis by microglial cells or macrophages is associated with plaque clearance. Hence, antibody therapy has the potential to treat Alzheimer's disease.
This is supported by non-Fc-mediated mechanisms being found to be associated with Aβ clearance in immunotherapy (Bacskai et al. (2002) J. Neurosci. 22:7873-7878; Das et al. (2003) J. Neurosci. 23:8532-9538).
One attempt at immunotherapy was the humanized antibody, Bapineuzumab or Bapi, developed by Pfizer and Johnson & Johnson. Bapi targets neurotoxic Aβ (Salloway et al. (2009) Neurology 73:2061-2070) at the extreme N-terminus in a helical conformation (Miles et al. (2013) Sci Rep 3:1-8) [doi:10.1038/srep01302]. Such Aβ forms with the N-terminal truncations comprise approximately 60% of Aβ deposits in the Alzheimer's diseased brains. Bapi was, however, shown to be toxic at higher doses.
Another antibody is Solanezumab (Eli Lilly). This antibody targets monomeric Aβ in the mid-region of the peptide and was partially efficacious in mild cases of Alzheimer's disease (Hardy (2014) N Engl J Med 370(4):377-378).
However, it appears that Solanezumab may be ineffective at reversing the symptoms in the later stages of Alzheimer's disease (Panza et al. (2014) Expert Opin Biol Ther:1-12 PMID 24981190).
Crenezumab (Genentech Inc.) also targets the mid-region of AB. It appears to stimulate microglia to a level sufficient to clear Aβ but without inducing an inflammatory response (Adolfsson et al. (2012) J. Neuroscience 32(28):9677-9689).
Ponezumab (Pfizer) targets the C-terminal end of Aβ1-40 but is unable to bind to elongated forms such as Aβ1-42 and Aβ1-43. Ponezumab was not efficacious in reducing biomarkers of Alzheimer's disease or cognitive decline (Liu et al. (2014) Mol Neurobiol:PMID 24733588). Another monoclonal antibody which has the same binding specificity as Ponezumab is referred to as Mab 2286 (Rosenthal et al. USSN 2011/038861, 2004/0146512 and 2007/0160616). Mab 2286 also does not bind to Aβ1-42 and Aβ1-43.
There is a need to further develop an immunotherapeutic approach to the treatment of disease conditions associated with toxic Aβ forms and their diagnosis.